Budesonide-incorporated inhalable lipid nanoparticles for antiTSLP nanobody mRNA delivery to treat steroid-resistant asthma.

Asthma exacerbations and steroid resistance occur due to disruption of the airway epithelium, limiting the effectiveness of corticosteroids. Although monoclonal antibodies have progressively emerged as adjunctive therapy for steroid-resistant asthma, there remains a clinical need for targeted anti-inflammatory therapies with better efficacy and fewer off-target effects. Here, we propose the ASCEND (Alternative Steroids Co-delivering with mRNA Encoding Nanobodies) approach, which utilizes inhalable lipid nanoparticles formulated with budesonide (iLNPBUD5) to deliver mRNA encoding a thymic stromal lymphopoietin nanobody (mnbTSLP) for the treatment of steroid-resistant asthma. Upon nebulization, mnbTSLP-iLNPBUD5 targets the lungs, enhancing antiTSLP nanobody production while delivering budesonide. This combined therapy reduces airway inflammation, remodeling, and hyperresponsiveness in murine models. Additionally, mnbTSLP restores the sensitivity of steroid-resistant asthmatic mice to budesonide by inhibiting key inflammatory pathways. The ASCEND approach shows superior effects compared to corticosteroid or antiTSLP antibody treatments, offering a promising strategy for steroid-resistant asthma and potentially other respiratory diseases.